{"paper_id":"0e835196-cbbb-4ea1-89aa-8a48e05d91a0","body_text":"The technique of embryo transfer is crucial and requires great attention and careful\nthought. Pregnancy after an embryo transfer (ET) depends on a number of factors,\nincluding embryo quality, endometrial receptivity, and embryo transfer technique\nitself.\nHistorically, embryo transfer methods have received little attention and minimal data\nhas been published on the subject. The reason for this is their apparent simplicity.\nNevertheless, difficult transfer procedures occur frequently and have been shown to\ndecrease pregnancy rates significantly. It has been reported that embryo transfer is\ninevitably traumatic and difficult to 5-7% of patients in assisted reproduction\ntreatment.( Tur-Kaspa  et al. ,\n1998 ;  Wood  et al .,\n1985 ). Moreover, in about one percent of the cases the transcervical\nroute may be nearly impossible to use, even by experienced practitioners, mainly due\nto anatomical and pathological cervical disorders such as congenital stenosis,\natresia or previous trachelectomy ( Healy  et\nal. , 2015 ;  Wood  et\nal. , 1985 ).\nPhysicians facing such scenario might have one of the following options: (i) carry on\nand perform the various maneuvers available and thus experience a very difficult and\ntraumatic transcervical embryo transfer (TCET); (ii) call off the fresh embryo\ntransfer and perform a frozen embryo transfer at a later occasion after cervical\ndilatation (with or without hysteroscopy), hoping it will alleviate the difficulty;\nor (iii) attempt a transmyometrial embryo transfer (TMET) if the other options\nfailed. Although applicable to only a few cases, the transmyometrial approach might\nbe considered as a possibility for performing embryo transfers in cases where\ntranscervical embryo transfer is very difficult to perform.\nThe aim of this study was to report our experience with this technique and analyze\nits causes, results and complications.\n\nSince 1993, 39 women (40 cycles of assisted reproductive technology treatment) were\noffered transmyometrial embryo transfers in a tertiary ART clinic (FIV Clinic) in\nBarcelona, Spain. The standard clinical protocol in effect at the clinic\ncontemplates TMET as the fifth alternative step for difficult/impossible\ntranscervical embryo transfers.\nTMET was performed mainly because transcervical embryo transfer (TCET) was an\nunviable option due to unmanageable cervical stenosis (37/39 patients) or other\ncervical anatomy abnormalities (2/39).\nAll patients but one received controlled ovarian stimulation with recombinant FSH\ninjections (Gonal F Merck SL). In 35/39 women, a long agonist protocol was used to\nachieve ovarian stimulation. Antagonist protocol was prescribed to three patients.\nOne case came from a natural cycle.\nOocyte maturation in the included patients was triggered by a single dose of\nrecombinant human chorionic gonadotropin (r-HCG) (Ovitrelle, 250mcg, Merck SL),\nbased on established estradiol levels and follicular diameters (leading follicle\nsize of 18mm). Thirty-four to 36 hours later, transvaginal ultrasound-guided\nfollicle aspiration (5MHz transvaginal probe, Aloka) was performed with the patients\nunder anesthesia. Daily vaginal micronized progesterone (Utrogestan, SEID Lab) as\nluteal support was initiated for all patients from the day of oocyte retrieval.\nWith respect to embryo transfer, the same protocol has been followed in the clinic\nsince 1993. Embryo transfer is usually performed transcervically with a flexible\ncatheter (Flexible Cook Catheter / Flexible Wallace Catheter). Initially a soft\nembryo transfer catheter is used because there is good evidence (Grade A) indicating\nit improves IVF embryo transfer pregnancy rates ( Practice Committee of the American Society for Reproductive Medicine,\n2017 ). When ET is not possible, a consistent inner guide is introduced\ninto the catheter to facilitate entrance into the external cervical os. When the\ncervix cannot be bypassed, a Pozzi tenaculum forceps is used to optimize cervix\ntraction. If these three maneuvers fail, a fourth and last attempt to transfer\nembryos transcervically is performed through mechanical cervical dilatation. In this\nlast step, complications such as uterine perforation or creation of false cervical\npassages must be considered. When these four attempts are unsuccessful, TMET is\nindicated.\nWhen the patient is suspected for cervical distortion or stenosis, a mock ET at the\ntime of oocyte retrieval is often performed. The method described by  Coroleu  et al . (2000)  for\nultrasound-guided transcervical intrauterine transfer has become the gold standard.\nVisualization has been shown to improve outcomes in transcervical ET. Ultrasound\nguidance allows accurate assessment of catheter position, thus helping physicians\nlead their way into the endometrial cavity. Cases of failed transcervical embryo\ntransfer decreased significantly, along with the need for TMET.\nIn our center, transmyometrial embryo transfer is performed as described by  Kato  et al . (1993) , with the\nTowako transfer set (Towako ®  needle, Cook, USA) ( Cook Medical, 2010 ). The procedure is performed\nwith the patient sedated and with an empty bladder in dorsal lithotomy position. In\nthe procedure, a transvaginal ultrasound probe with a Towako needle attached to the\nneedle holder of the vaginal probe is used ( Healy\n et al ., 2015 ). Under direct visualization the uterus\nis scanned until the endometrial stripe is found; then the needle is inserted\ntransmyometrially until it reaches the outer layer of the endometrium at the level\nof the uterine fundus ( Kato  et al .,\n1993 ) ( Figure 1 ). An embryologist\nthen loads the embryo suspended in culture medium with the inner catheter and\ninserted into the needle in a way that the catheter protrudes 1mm beyond the tip of\nthe needle. The embryo is gently injected inside the endometrial cavity\napproximately 1.5cm from the fundus of the uterus; in cases of retroverted uterus,\nthe needle may be inserted through the posterior fornix, posterior uterine wall or\nposterior endometrial border ( Khairy  et\nal ., 2016 ;  Akhtar  et\nal ., 2015 ). The embryo transfer is confirmed by a flow of\nechogenic fluid clearly seen inside the endometrial cavity ( Figure 2 ). Finally, an embryologist checks whether the catheter\nstill holds embryos before discarding it.\nFigure 1 Transmyometrial ET procedure. The needle is inserted across the anterior\nmyometrial wall aiming the endometrium stripe\nTransmyometrial ET procedure. The needle is inserted across the anterior\nmyometrial wall aiming the endometrium stripe\nFigure 2 Transmyometrial ET procedure. Embryos suspended in culture medium are\ngently injected in the endometrial cavity approximately 1.5 cm from the\nfundus of the uterus. Embryo transfer is confirmed by a flow of\nechogenic fluid clearly seen inside the uterine cavity\nTransmyometrial ET procedure. Embryos suspended in culture medium are\ngently injected in the endometrial cavity approximately 1.5 cm from the\nfundus of the uterus. Embryo transfer is confirmed by a flow of\nechogenic fluid clearly seen inside the uterine cavity\nThe patients rest for approximately two hours until they are completely recovered,\nand are then discharged to go home on the same day of the procedure.\n\nBaseline characteristics are described in  Table\n1 . The enrolled female patients had a mean age of 34 years and a mean\nbaseline FSH level of 6.89 IU/mL.\nClinical characteristics and IVF outcomes for patients offered\ntransmyometrial embryo transfer (TMET).\nResults are shown as mean and 95% CI.\nResults are shown as median and p25-p75 interquartile range.\nUnexplained infertility (32.5%) was the leading cause of couple infertility, followed\nby male factor (27.5%), endometriosis (20%), tubal factor (12.5%), and donor sperm\n(7.5%).\nWith respect to ART outcomes, the median number of retrieved oocytes was 7.50, and a\nmean of 2.63 embryos were transferred.\nForty TMET procedures have been performed in our center since 1993, yielding an\nimplantation rate of 9.5% (ten pregnancies from 105 transferred embryos). In terms\nof clinical outcomes, the pregnancy rate was 25% (10/40). Unfortunately, three\npregnancies ended in miscarriage (30%). Since there were two twin pregnancies, the\nlive birth rate was 22.5% (9/40).\nTMET is a relatively quick and easy procedure to perform. Pain, bleeding, infection\nand injuries to adjacent organs are possible complications. No major complications\nwere reported in our study. However, managing missed abortions may be somewhat\ncomplicated in these patients. Cervical dilatation and uterus aspiration might not\nbe easily performed, and alternative ways to approach missed abortions must be\npursued by clinicians.\nDuring the first 10 years of the studied period, TMET accounted for approximately\n7.8% (28 TMET) of all embryo transfers (n=3587) in our center. As described above,\nafter the publication by  Coroleu  et\nal . (2000)  ultrasound-guided transcervical embryo transfer\nbecame the gold standard, driving down the use of TMET to 1.2% (12/9534).\nThe analysis of clinical outcomes revealed an improvement in pregnancy rates by TMET\nthroughout a 25-year observation period, despite the drop in the use of the\nprocedure. An analysis of five-year periods ( Figure\n3 ) showed that the clinical pregnancy rate of TMET increased from 10%\n(1993-1997) to 14% (1998-2002), 20% (2008-2012), and 50% (2013-2017). This last\nclinical pregnancy rate (50%) was calculated from very few TMET procedures (n=4). No\nTMET procedure was performed from 2008 to 2012.\nFigure 3 Comparative pregnancy rate between general Clinical Pregnancy Rate (blue\ncolumns) and Clinical Pregnancy Rate by TMET (red columns)\nComparative pregnancy rate between general Clinical Pregnancy Rate (blue\ncolumns) and Clinical Pregnancy Rate by TMET (red columns)\nThese findings were consistent with the progression of clinical pregnancy rates\nobserved in our center during the studied period, as discussed below.\n\nSince the first pregnancy using IVF was achieved nearly 30 years ago, many features\nof the procedure have been significantly changed. In contrast, embryo transfer has\nremained relatively unaltered.\nToday, one of the most challenging issues arising from ET involves the management of\nvery difficult or impossible transcervical embryo transfer (TCET) procedures. Since\nthere is no consensus over what constitutes a difficult ET, an accurate comparison\nof studies becomes even more troublesome ( Phillips\n et al. , 2013 ;  Akhtar\n et al ., 2015 ). Nonetheless, it has been shown that\nthe clinical pregnancy rate decreases progressively as additional maneuvers are\nperformed during ET ( Kava-Braverman  et\nal ., 2017 ). An alternative technique for embryo transfer\nthat bypasses the cervical canal is the Towako method, otherwise known as TMET. This\nis potentially a good option for patients with severe cervical stenosis or history\nof difficult embryo transfers.\nTransmyometrial embryo transfers have been reported in 15 studies: 11 case reports, 3\ncase series, and one randomized clinical trial ( Khairy  et al ., 2016 ;  Huberlant  et al ., 2014 ;  Muñoz  et al ., 2014 ;  Sullivan-Pyke  et al ., 2014 ;  Lin  et al. , 2010 ;  Jamal  et al ., 2009 ;  Ohl  et al ., 2009 ;  Xu  et al ., 2009 ;  Lai  et al ., 2001 ;  Anttila  et al ., 1999 ;  Lesny  et al ., 1999 ;  Asaad & Carver-Ward, 1997 ;  Groutz  et al ., 1997 ;  Sharif  et al ., 1996 ;  Kato  et al ., 1993 ). The\nresults reported in these studies are controversial because the inclusion criteria\nare heterogeneous. Even though TMET was performed in cases of difficult conventional\nET, it is hard to accurately describe the degree of difficulty encountered in the\nprocedure. This might explain the discordant clinical pregnancy rates published in\nthese studies.\nAs mentioned above, several aspects of a difficult TCET may reduce the clinical\npregnancy rate, including endometrial injury or the induction of uterine\ncontractions. Physicians have the option to carry on with the TCET procedure\nprogressively with additional maneuvers, knowing that the pregnancy rate might\ndecrease with each maneuver, or patients may be offered to proceed with embryo\nfreezing (or re-freezing) and then have an optimized TCET using the cervical\napproach or with anesthesia before reattempting the TCET. Further studies are\nrequired to compare those approaches.\nIn our study the clinical pregnancy rate was lower (25%) when compared to the 32%\nreported by  Khairy  et al .\n(2016)  and the 36.5% by  Kato  et\nal . (1993) . However, we must point out that the poorer\noutcomes seen in our series might be explained by the systematic use of additional\nmaneuvers before TMET ( Pasqualini & Quintans,\n2001 ;  Ghazzawi  et al., \n1999 ). One study reported that TMET led to increased junctional zone\ncontractions, which is believed to decrease the chance of implantation. However, the\nsame study showed that very difficult embryo transfers also triggered zone\ncontractions with similar frequency and amplitude ( Biervliet  et al ., 2002 ).\nThe use of ultrasound guidance in embryo transfers started in 2001, leading to a\ndecrease in the number of TMET procedures. Nearly two thirds (67.5%) of our cases\nwere performed prior to the use of ultrasound guidance during the embryo transfer.\nThe strengths of this study lie in the number of cases included - all of which from\nthe same center - and the homogeneous inclusion criteria adopted, according to which\nall TMET procedures were performed after the same sequence of maneuvers. On the\nother hand, a weakness is the retrospective nature of our cases, many of which are\nnot very recent.\nAlthough suitable for a few cases, TMET might be considered as a viable option in\ncases where TCET is difficult to perform. TMET is not a novel option, but it should\nbe thought of as a useful approach to help women with troublesome conventional\nembryo transfers. Even though improvements in catheters and embryo transfer\nconditions with the use of hysteroscopy have relegated TMET to a lesser position,\nthe procedure might still be useful in certain cases.\n\nThis retrospective single-center study summarized our 25-year experience with TMET.\nOur results reflect the cases of a group of patients with great difficulty in\nconventional ET, in which the same maneuvers were performed before proceeding to\nTMET. The results published herein might have been better if TMET had been performed\nearlier to minimize the traumatic effect of other maneuvers.","source_license":"CC-BY-4.0","license_restricted":false}